Hemodynamic mechanisms in patients with atrial functional and structural mitral regurgitation based on 4D flow cardiac MRI

Introduction

Atrial functional mitral regurgitation (AFMR) can cause mitral regurgitation (MR) and tricuspid regurgitation (TR) without structural valve abnormalities, due to atrial enlargement and annular dilatation. Also, the number of patients with atrial fibrillation (Af) is increasing with the aging population, and more than 1% of people in industrialized countries suffer from chronic Af (1,2), which often causes MR and TR without structural valve abnormalities. Af causes atrial enlargement, which leads to valve tethering due to atrioventricular annular enlargement, and has become an emerging disease concept of “AFMR” (3-5) in the Japanese cardiovascular guidelines in 2020 (6). However, because the disease concept is new, there is insufficient evidence regarding the indications for surgery. Therefore, a hemodynamic assessment of this complex pathophysiology should be performed beyond conventional ultrasonography measurements.

Recently, four-dimensional (4D) flow cardiac magnetic resonance imaging (MRI) has been used to assess hemodynamics and evaluate a wide range of cardiovascular diseases, such as aortic disease, valvular heart disease, heart failure, pulmonary hypertension, and congenital heart disease, based on the concept of energy loss (EL) (7-14). The purpose of the present study was to assess the right and left ventricular function and pulmonary and systemic hemodynamics by comprehensive assessment of AFMR and structural MR (StMR) for mitral prolapse using 4D flow MRI and to elucidate the pathophysiological mechanism of AFMR. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1752/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Osaka Metropolitan University (No. 2021-267) and informed consent was taken from all the patients.

Patient selections

This study was a prospective study. 10 patients with AFMR due to chronic Af and 10 with StMR due to mitral cord prolapse were selected as controls. The AFMR patients with chronic Af were selected based on surgical eligibility determined at Osaka Metropolitan University Hospital, taking into account not only the severity of MR alone, but also cardiac echocardiographic and symptom findings, such as New York Heart Association (NYHA) classification. TR was not included in the selection criteria. The StMR group consisted of patients with MR due to prolapse, with moderate or higher severity, who were determined suitable for surgery at our institution based on cardiac echocardiographic findings.

At Osaka Metropolitan University Hospital, 135 patients who underwent mitral valve surgery between November 2022 and July 2024 were enrolled, excluding those with mitral stenosis (MS), leaving 132 patients with MR. From the remaining 82 cases, excluding those with mild or severe aortic valve or pulmonary valve disease, ischemic cardiomyopathy, dialysis, or congenital disease (atrial septal defect or patent foramen ovale), 20 cases (10 AFMR cases and 10 StMR cases) who consented to participate in the study were selected. All patients who underwent MRI also underwent surgery.

Patient characteristics are shown in Table 1. Characteristics, including age, sex, NYHA, number of smokers, drinking, hypertension, hyperlipidemia, diabetes mellitus, MR on echocardiogram (> moderate)/TR on echocardiogram (> moderate), N-terminal pro-B-type natriuretic peptide (NT-proBNP) (pg/mL), and Af duration (years), were evaluated. Af duration was defined as the period from the onset of symptoms or electrocardiogram (ECG) findings to the time of MRI examination.

They were performed preoperative 4D flow cardiac MRI.

Cardiac MRI analysis

MRIs were performed using a Siemens (MAGNETOM Viad, XA50, Siemens Healthcare Japan, Tokyo, Japan) with the following settings. Magnetic field strength: 3 T; flip angle: 8°; field of view (FOV): 340 (frequency direction) × 238 (phase direction); acquisition matrix: 160 (frequency direction) × 90 (phase direction); volume orientation: sagittal; repetition time/echo time: 5.28 mc/2.76 ms; spatial resolution: acquisition voxel size 2.66 mm × 2.13 mm × 6.15 mm; reconstruction voxel size 2.13 mm × 2.13 mm × 4 mm; combined high-speed imaging method: GRAPPA 2; velocity encoding (VENC): 150 cm/s. A contrast agent was not used. Temporal resolution/number of time phases: for a case with an R-R interval of 1,000 ms (heart rate 60 beats per minute), the temporal resolution per phase is 40.64 ms, and the number of phases is 23. We do not use respiratory synchronization and attach the ECG and perform prospective gating ECG synchronization. The 4D flow imaging and EL calculations were performed using a dedicated post-processing software for 4D flow MRI (iTFlow; Cardio Flow Design Inc., Tokyo, Japan). Systemic and pulmonary heart systems’ hemodynamics were visualized using time-resolved three-dimensional (3D) stream velocity lines. Flow acceleration with over-VENC aliasing was manually corrected with phase shift. We assessed the systolic and diastolic viscous flow EL between systemic and pulmonary heart systems using the software mentioned above. The endpoints were left cardiac output (ltCO)/right cardiac output (rtCO) (L/min), left cardiac index (ltCI)/right cardiac index (rtCI) (L/min/m²), MR/TR fraction (%), systemic (left side) EL (ltEL)/pulmonary (right side) EL (rtEL) (Mw), left ventricular end-systolic volume (LVESV)/left ventricular end-diastolic volume (LVEDV)/right ventricular end-systolic volume (RVESV)/right ventricular end-diastolic volume (LVEDV) (mL), left atrial volume (LAV) (mL), LAV index (LAVI) (mL/m²), EL/cardiac output (CO) ratio were calculated. The relationship between each factor was examined using plots and statistical analyses. The measurement method of “EL” is defined as EL = 1/2µ∫_ΩΣ_i,j(∂u_i/∂x_j +∂u_j/∂x_i)²d_Ω, where i and j indicates arbitrary direction of anterior-posterior (AP), superior-inferior (SI), and right-left (RL), and x_i and u_i indicates arbitrary direction of the space and velocity vector, respectively, and Ω is a notation for representing a region, regardless of dimension (in two dimensions, it denotes an area integral, and in three dimensions, it denotes a volume integral). They can be measured from visualized blood flow.

Statistical analysis

All statistical analyses were performed using EZR (EZR on R Commander, programmed by Y Kanada, ver1.55). In both groups, the outcome was a continuous variable that did not follow a normal distribution. Therefore, the Mann-Whitney U test was used to compare the differences between the two groups (median, interquartile range), and Spearman’s correlation coefficient (ρ value) was used for correlation comparison.

Results

Flow streamlines with velocity contours and flow EL in each disease group during one cardiac cycle are shown in Figure 1. MR/TR jet and EL in the dilated atrioventricular space were observed in the systemic and pulmonary systems of AFMR patient (Figure 1A), and MR/TR and EL were observed in StMR patient (Figure 1B). Various parameters were measured for each group (Table 2).

Figure 1 Flow streamline and EL in systolic phase in systemic and pulmonary circulation. (A) Systemic and pulmonary flow image of AFMR patient. The central MR and high EL at the same area, and TR and high EL at the same area. (B) Deflection MR and high EL in the same area, while TR and EL are low. AFMR, atrial functional mitral regurgitation; EL, energy loss; MR, mitral regurgitation; TR, tricuspid regurgitation.

Although there was no significant difference, ltEL tended to be lower in the AFMR group than in the StMR group [AFMR: 3.34 (1.96–6.46) mW, StMR: 7.13 (4.75–9.72) mW, P=0.08]. On the other hand, rtEL tended to be higher in the AFMR group than in the StMR group [AFMR: 2.43 (1.87–4.03) mW, StMR: 1.70 (1.18–2.13) mW, P=0.17], also CO and CI were significantly lower in the AFMR group [CO: AFMR: 5.01 (4.53–6.13) L/min, StMR: 8.54 (7.51–11.11) L/min, P<0.001; CI: AFMR: 3.54 (3.17–3.98) L/min/m², StMR: 5.47 (4.37–6.09) L/min/m², P=0.007].

Figure 2 shows the relationship between EL for the systemic system/pulmonary system and CO in the AFMR and StMR groups. The EL for both groups was higher than that in the healthy range [EL: 1.65±0.45 mW, CO: 5.71±1.9 L/min (7)]. Lower CO and EL were found in the bilateral system in the AFMR group than those in the StMR group.

Figure 2 Plots of relation between EL for systemic system/pulmonary system and CO in the AFMR and StMR groups. Both ELs were found higher in both groups than those in the healthy range. On the other hand, lower CO and EL were found in the bilateral system in the AFMR group than that in the StMR group. AFMR, atrial functional mitral regurgitation; CO, cardiac output; EL, energy loss; ltEL, systemic (left side) energy loss; rtEL, pulmonary (right side) energy loss; StMR, structural mitral regurgitation.

Regarding the heart chamber volume, LVEDV was significantly lower in the AFMR group [AFMR: 134.6 (114.1–177.3) mL, StMR: 209.0 (190.1–255.6) mL, P=0.01]. Furthermore, when evaluating EL density as EL/various heart chamber volumes, ltEL/LAV and ltEL/RVEDV, rtEL/LVEDV were significantly lower in the AFMR group [ltEL/LAV: AFMR: 0.025 (0.016–0.036) mW/mL, StMR: 0.084 (0.057–0.11) mW/mL, P<0.001; ltEL/RVEDV: AFMR: 0.017 (0.011–0.023) mW/mL, StMR: 0.042 (0.024–0.061) mW/mL, P<0.001; rtEL/LVEDV: AFMR: 0.014 (0.0086–0.026) mW/mL, StMR: 0.0083 (0.0059–0.011) mW/mL, P=0.02]. Furthermore, the CO/LAV and CO/RVEDV were significantly lower in the AFMR group [CO/LAV: AFMR: 0.046 (0.025–0.062) L/min/mL, StMR: 0.11 (0.097–0.12) L/min/mL, P<0.001; CO/RVEDV: AFMR: 0.032 (0.017–0.036) L/min/mL, StMR: 0.051 (0.042–0.059) L/min/mL, P<0.001].

Regarding accompanied TR, TR fraction was significantly more severe in the AFMR group [AFMR: 56.1% (39.5–69.2%), StMR: 29.0% (20.9–37.9%), P=0.01].

Table 3 summarizes the correlations between the heart chamber volume and degree of valve regurgitation for CO and EL in both heart systems in each group. As shown in Table 3, AFMR showed a positive correlation with ltEL and the volume of both ventricles, and rtEL showed a positive correlation with right ventricular volume. In contrast, although there was no significant difference in the TR fraction, the CO levels tended to decrease as regurgitation increased. Overall, a positive correlation was observed between CO and left ventricular volumes. Positive correlations were observed between the ltEL and MR fractions, and between the rtEL and TR fractions (P<0.05).

Table 4 showed correlation between Af duration period and each parameter. In this study, the Af duration period and rtEL/CO, as well as the ltEL/LVEDV, were not significantly different but seemed to be positively correlated. However, no correlation was found for the other parameters.

Discussion

According to the guidelines, surgical intervention is recommended only when MR and/or TR are severe in the regurgitation grade, despite the fact that approximately 20–25% of long-term Af patients have more than moderate MR and/or TR (6), and that even moderate-grade regurgitation cases repeat exacerbations of heart failure within several years despite careful medication therapy. In other words, the prognosis of AFMR should not be considered only by the regurgitation grade because of the complexity of the disease.

According to a previous study, the mean ltEL and rtEL values of healthy people were reported to be 1.65±0.45 and 1.02±0.29 mW (7). In Table 1, compared to these values, the ltEL and rtEL values of patients with both AFMR and StMR, with surgical indication based on conventional ultrasonography findings, were higher compared those of reference value, and they increased according to the severity of valve regurgitation.

The significantly lower CO/CI in the AFMR group in the present study may be due to the following two reasons. First, expansion of the LAV due to chronic atrial fibrillation or RV volume may lead to the physical dysfunction of left ventricular dilatation. The LVEDV was significantly smaller in the AFMR group than that in the StMR group, whereas the LAV and RV volumes tended to be higher. In addition, Table 3 shows that the largest difference between the two groups was the correlation of ltEL to right ventricular volume, suggesting that right ventricular volume may not simply be an effect of the pulmonary system alone and may be the basis of the AFMR pathophysiology as a ventricular-ventricular (VV) (15,16) interaction. Also, several reports have been published on right ventricular volume and cardiac workload (12,17,18). Regarding the relationship between right ventricular volume and ltEL, a positive correlation was also found in an analysis of healthy subjects (7), suggesting that the right chamber volume expansion may be associated with reduced left heart function and high-EL due to MR.

Second, low CO due to right-sided heart failure may have led to low LV preload. Table 2 reveals that the TR was more severe in the AFMR group, which may be a contributing factor to the significantly higher pulmonary preload in the AFMR group. This is also because the rtEL/CO rate, as a qualitative measure of the pulmonary system, in the AFMR group was significantly higher than that in the StMR group (Table 2). Moreover, Table 4 may not have enough statistical power due to the small number of patients; an association between Af duration and the rtEL/CO rate has been observed (P=0.056). The pathological condition of AFMR leads to a difference between AFMR and StMR, because AFMR is essentially a disease that affects the TR and pulmonary system. This finding is consistent with the results presented in Tables 1,2.

The EL in the left ventricular system due to MR affects right ventricular enlargement in AFMR, which may indicate VV interaction in this pathology. The essence of VV interaction cannot be understood without looking at the relationship between ltEL and the right ventricular volume.

Limitation

MRI measurements are quantitative and have limitations in spatial and temporal resolution, and errors depend on the handler skill. However, incorporating turbulence into the measurement may result in overestimation or underestimation as an interobserver error. For the accurate estimation of dominant flow in the ventricle and large vessels, VENC was set 1.5 m/s in the present study, which is usually too low compared with the regurgitation jet. Thus, even though a method of de-aliasing with phase shift was applied in the flow acceleration, the jet velocity estimation was inaccurate.

In addition, since the severity of TR was not available in this study, we were not able to determine the extent to which the severity of TR affected the MR and EL. More studies are needed in this regard in the future.

In this case, the focus was on the mitral and tricuspid valves. However, it should be noted that the pathophysiology becomes more complex when aortic and pulmonary valve disease, shunt disease, and other conditions are involved. In cases with abnormally enlarged atria or ventricles, normal blood flow is lost and turbulent flow becomes more complicated and difficult to measure and evaluate with pure valve regurgitation. Therefore, the evaluation of these patients may be more difficult.

Also, it is certainly impossible to ignore the fact that the AFMR group is significantly older, and this may be a contributing factor to the reduction in CO and CI. Therefore, it is considered necessary to conduct age-specific analyses in the future by accumulating more cases.

Finally, in this study, the right atrium (RA) volume was not calculated due to the vagueness of the structural border between the RA and the inferior vena cava (IVC) or superior vena cava (SVC). In the future, we will define the border of the RA, IVC, and SVC and calculate the RA volume.

Conclusions

4D flow MRI is a new tool that may provide a comprehensive assessment of cardiac function and hemodynamics in mitral and tricuspid valve regurgitation disease.

AFMR tends to have lower cardiac function than StMR, with a higher pulmonary system load and hemodynamics in which the enlarged right ventricle compresses and drains the left ventricle, thereby increasing EL in the systemic system.

In AFMR, the longer the duration of Af, the higher the EL for a small left ventricle.

Acknowledgments

We would like to thank Editage (https://www.editage.jp/) for English language editing.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1752/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1752/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1752/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1752/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the ethics committee of Osaka Metropolitan University (No. 2021-267) and informed consent was taken from all the patients.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Inoue H, Fujiki A, Origasa H, et al. Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol 2009;137:102-7. [Crossref] [PubMed]
2. Yang C, Kong Y, Liu X, et al. Global, regional, and national burden of atrial fibrillation and atrial flutter in the working-age population from 1990 to 2021: A systematic analysis based on 2021 global burden of disease data. Am J Prev Cardiol 2025;24:101322. [Crossref] [PubMed]
3. Takahashi Y, Abe Y, Sasaki Y, et al. Mitral valve repair for atrial functional mitral regurgitation in patients with chronic atrial fibrillation. Interact Cardiovasc Thorac Surg 2015;21:163-8. [Crossref] [PubMed]
4. Takahashi Y, Shibata T, Hattori K, et al. Extended posterior leaflet extension for mitral regurgitation in giant left atrium. J Heart Valve Dis 2014;23:88-90.
5. Abe Y, Akamatsu K, Ito K, et al. Prevalence and Prognostic Significance of Functional Mitral and Tricuspid Regurgitation Despite Preserved Left Ventricular Ejection Fraction in Atrial Fibrillation Patients. Circ J 2018;82:1451-8. [Crossref] [PubMed]
6. Izumi C, Eishi K, Ashihara K, et al. JCS/JSCS/JATS/JSVS 2020 Guidelines on the Management of Valvular Heart Disease. Circ J 2020;84:2037-119. [Crossref] [PubMed]
7. Nakaji K, Itatani K, Tamaki N, et al. Assessment of biventricular hemodynamics and energy dynamics using lumen-tracking 4D flow MRI without contrast medium. J Cardiol 2021;78:79-87. [Crossref] [PubMed]
8. Itatani K. When the blood flow becomes bright. Eur Heart J 2014;35:747-752a.
9. Schäfer M, Di Maria MV, Jaggers J, et al. Hemi-Fontan and bidirectional Glenn operations result in flow-mediated viscous energy loss at the time of stage II palliation. JTCVS Open 2023;16:836-43. [Crossref] [PubMed]
10. Morr-Verenzuela CI, Fuentes Latorre E, Prat-González S. 4D-flow CMR assessment: a key tool in corrected congenital heart diseases. Rev Esp Cardiol (Engl Ed) 2024;77:354-5. [Crossref] [PubMed]
11. Grafton-Clarke C, Thornton G, Fidock B, et al. Mitral regurgitation quantification by cardiac magnetic resonance imaging (MRI) remains reproducible between software solutions. Wellcome Open Res 2021;6:253. [Crossref] [PubMed]
12. Shiina Y, Nagao M, Itatani K, et al. 4D flow MRI-derived energy loss and RV workload in adults with tetralogy of Fallot. J Cardiol 2024;83:382-9. [Crossref] [PubMed]
13. Itatani K, Sekine T, Yamagishi M, et al. Hemodynamic Parameters for Cardiovascular System in 4D Flow MRI: Mathematical Definition and Clinical Applications. Magn Reson Med Sci 2022;21:380-99. [Crossref] [PubMed]
14. Therrien J, Provost Y, Merchant N, et al. Optimal timing for pulmonary valve replacement in adults after tetralogy of Fallot repair. Am J Cardiol 2005;95:779-82. [Crossref] [PubMed]
15. Schwarz K, Singh S, Dawson D, et al. Right ventricular function in left ventricular disease: pathophysiology and implications. Heart Lung Circ 2013;22:507-11. [Crossref] [PubMed]
16. Kim SM, Randall EB, Jezek F, et al. Computational modeling of ventricular-ventricular interactions suggest a role in clinical conditions involving heart failure. Front Physiol 2023;14:1231688. [Crossref] [PubMed]
17. Shiina Y, Itatani K, Inai K, et al. Energy loss and adults with congenital heart disease: a novel marker of cardiac workload beyond right ventricular size. Cardiovasc Diagn Ther 2024;14:1202-9. [Crossref] [PubMed]
18. Gabbert DD, Trotz P, Kheradvar A, et al. Abnormal torsion and helical flow patterns of the neo-aorta in hypoplastic left heart syndrome assessed with 4D-flow MRI. Cardiovasc Diagn Ther 2021;11:1379-88. [Crossref] [PubMed]